Zhong Wanyu, Zhu Guanghao, Lu Dingzhuo, Wang Linmei, Zhang Binyuan, Su Zhonghao, Qin Zhenxia
Department of Anatomy, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Biochem Pharmacol. 2025 Sep;239:117034. doi: 10.1016/j.bcp.2025.117034. Epub 2025 Jun 6.
Oxidative stress and neuroinflammation are undoubtedly common etiologies of neurodegenerative diseases, contributing to the disease progression. Madecassoside (MA), a triterpenoid saponin component derived from herbal medicine Centella asiatica, exhibits multiple biological properties including anti-oxidative and anti-inflammatory activities in neurodegenerative disease models. In addition, MA improved the neurodegeneration of protein L-isoaspartyl methyltransferase (PIMT/PCMT1) knockout mice. However, the exact neuroprotective mechanism of action and the targets of MA in PIMT deficient mice remain largely elusive. To address this, the oxidative stress indices including malondialdehyde (MDA), superoxide dismutase (SOD), and peroxiredoxins-2 (PRDX2) levels were detected by using a biochemical method. Pro-inflammatory cytokine (Caspase-1) levels were measured via RT-qPCR. The activation of microglia and astrocyte was examined through immunofluorescence staining of Iba1 (microglia marker) and GFAP (astrocyte marker). The results indicated that PIMT deficiency induced hippocampal oxidative stress and neuroinflammation. Intriguingly, besides the peroxidase activity, the redox-oligoforms of PRDX2 with potential hotspots for the formation L-isoaspartate (L-isoAsp) residue was also affected significantly by PIMT deficiency. In addition, PRDX2 was co-localized with Iba1 and GFAP. Collectively, it was suggested PRDX2 might be involved in aberrant redox homeostasis and microglial neuroinflammation of PIMT deficient mice, which could be improved by MA. Taken together, these findings not only provide novel insight into the underlying mechanism of PIMT deficiency-induced neurodegeneration, but also support the notion that the PIMT-PRDX2 axis is a promising potential therapeutic target for MA as anti-neurodegeneration agent.
氧化应激和神经炎症无疑是神经退行性疾病常见的病因，会促使疾病进展。积雪草苷（MA）是从草药积雪草中提取的一种三萜皂苷成分，在神经退行性疾病模型中具有多种生物学特性，包括抗氧化和抗炎活性。此外，MA改善了蛋白质L-异天冬氨酸甲基转移酶（PIMT/PCMT1）基因敲除小鼠的神经退行性变。然而，MA在PIMT缺陷小鼠中的确切神经保护作用机制和靶点仍不清楚。为了解决这个问题，采用生化方法检测了包括丙二醛（MDA）、超氧化物歧化酶（SOD）和过氧化物还原酶-2（PRDX2）水平在内的氧化应激指标。通过RT-qPCR检测促炎细胞因子（半胱天冬酶-1）水平。通过对Iba1（小胶质细胞标志物）和GFAP（星形胶质细胞标志物）进行免疫荧光染色，检测小胶质细胞和星形胶质细胞的激活情况。结果表明，PIMT缺陷会诱导海马体氧化应激和神经炎症。有趣的是，除了过氧化物酶活性外，可以形成L-异天冬氨酸（L-isoAsp）残基的潜在热点的PRDX2氧化还原寡聚体形式也受到PIMT缺陷的显著影响。此外，PRDX2与Iba1和GFAP共定位。总的来说，提示PRDX2可能参与了PIMT缺陷小鼠异常的氧化还原稳态和小胶质细胞神经炎症，而MA可以改善这种情况。综上所述，这些发现不仅为PIMT缺陷诱导神经退行性变的潜在机制提供了新的见解，也支持了PIMT-PRDX2轴作为MA抗神经退行性变药物的一个有前景的潜在治疗靶点的观点。
